Therapeutic potential of YAP1 activation in nagashima-type palmoplantar keratosis: Rescue of epidermal pathology in human skin organoid models

Summary: Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive genetic skin disorder characterized by keratosis of the palmar and plantar regions, due to mutations in the <i>SERPINB7</i> gene. However, the precise mechanisms underlying the pathogenesis of NPPK remain elusive. This study found no direct interaction between SERPINB7 and proteolytic enzymes. However, our findings demonstrated that SERPINB7 mutation significantly impaired keratinocyte proteolysis by downregulating the expression of kallikreins (KLKs) and matrix metalloproteinases (MMPs) in the epidermis of NPPK patients. Mechanistically, SERPINB7 mutations inhibited keratinocyte glycolysis by suppressing hexokinase 1 (HK1) activity, disrupting the activation and nuclear translocation of the transcription factor YAP1, and ultimately leading to decreased expression of KLKs and MMPs in keratinocytes. Furthermore, we established a pioneering three-dimensional skin organoid model carrying the SERPINB7 c.796C>T mutation that faithfully recapitulates human NPPK pathology at molecular and histological levels. Pharmacological YAP1 activation in this preclinical model significantly attenuated disease-associated phenotypic and biochemical abnormalities. These findings delineate a novel metabolic-transcriptional axis underlying NPPK pathogenesis and identify YAP1-targeted intervention as a promising therapeutic strategy for this dermatological disorder. Jun Liu¹, Wen Zheng¹, Tao Yang¹, Qiuping Zhang¹, Chao Yang¹, Bin Yang¹ 1. Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics